The present application relates to amino amides, peptides and peptidomimetics, and methods for preparing such compounds.
The unique roles of various peptides, including their function as extra-cellular messengers, hormones, neurotransmitters neuromodulators, and immune defense modulators, is well established. Consequently, the use of peptides or amino amides containing natural and unnatural amino acid units against many therapeutic targets is of continued interest. Numerous methods have been developed for the synthesis of amino amides or peptides both in solution and on a solid support (Bodanszky, M. Principle of Peptide Synthesis, 2nd Edition, Springer-Verlag, Berlin, 1993; Guillier, F.; Orain, D.; Bradley, M. Chem. Rev., 100:2091; 100:2091; 2000; Humphrey, J. M.; Chamberlin, A. R. Chem. Rev., 97:2243, 1997).
Due to difficulties resulting from the limited selectivity, stability, delivery and bioavailability of certain peptides, the design and synthesis of peptidomimetic molecules continues to be at the forefront of drug design and discovery and many peptidomimetic frameworks and methods for their synthesis have been developed (Babine, R. E.; Bender, S. L., Chem. Rev., 97:1359, 1997; Hanessian, S.; et al., Tetrahedron, 53:12789, 1997; Fletcher, M. D.; Cambell, M. C., Chem. Rev., 98:763, 1998).
Traditional peptide synthesis in both solution phase and solid phase involves the stepwise or iterative use of the following six transformations: (a) synthesis of amino acid units;(b) monoprotection of certain amino acid units at their N-terminus; (c) monoprotection of certain amino acid units at their C-terminus; (d) coupling of an N-protected and a C-protected amino acid unit via amide bond formation; (e) removal of the protecting group from the N-terminus; and (f) removal of the protective group from the C-terminus. A number of unconventional approaches to the synthesis of peptides have also been developed, including the use of the Ugi four-component condensation reaction of acids, aldehydes, isocyanides and amines (Waki, M.; Meienhofer, J. J. Am. Chem. Soc., 99:6075, 1977; Hoyng, C. F.; Patel, A. D. Tetrahedron Lett., 21:4795, 1980).
Among the drawbacks of the traditional approaches to peptides and peptidomimetics is the large number of required reaction steps and the difficulties in incorporating certain unnatural amino acid side chains, such as alkenyl, alkynyl, allenyl, aryl and heteroaryl groups.